The long term goal of my research program is to determine the molecular mechanisms by which extracellular signals regulate mesenchymal cell fate decisions. While the focus of my lab has been on defining the genetic program of adipogenesis and its regulation, we are now, in collaboration with Dr. Kurt Hankenson, extending this line of research to signals that determine whether multipotent cells differentiate into adipocytes or osteoblasts. We have pioneered investigations into the role of Wnt signaling as a potent, endogenously produced inhibitor of adipogenesis in cultured preadipocytes and in transgenic mice. An exciting part of the phenotype of mice that express Wnt10b from an adipocyte-specific promoter is that they have increased trabecular bone. This raises the possibility that inhibition of adipogenesis in marrow increases the number of marrow-derived mesenchymal stem cells (MSC) available for osteogenesis, and/or that Wnt10b directly stimulates differentiation of precursor cells into osteoblasts. Alternatively, a decrease in systemic leptin levels in the transgenic mice could result in enhanced bone mass, since leptin has been shown to be a negative regulator of bone formation. The goal of the proposed research is to test the hypothesis that Wnt10b increases bone formation by promoting osteoblast differentiation of MSC through a direct, local mechanism. To test this hypothesis we propose the following Specific Aims: (1) Determine whether enhanced bone mass results from an increase in bone formation rather than a decrease in osteoclast activity. (2) Determine whether Wnt10b promotes osteoblastogenesis directly, or whether effects are secondary to a decrease in adipose tissue and circulating leptin.